Aromatic ring-substituted steroids and preparation thereof



United States Patent Delaware No Drawing. Fiied June 5, 1961, Ser. No.114,653

33 Claims. (@Cl. 2613-6971) This invention relates to aromaticring-substituted steroids, and in particular it is concerned with4-hydroxy- [benzo-1,2:2,3-steroids], with esters thereof, withintermediates therefor, and with the preparation thereof.

It has been found that new arid useful compounds are produced when abenzene ring is fused to the 2- and 3- positions of a steroid, saidbenzene rin bearing a hydroxy or acy-loxy group in position para to the2-position of the steroid nucleus, and the steroid moiety having fromseventeen to about twenty-three carbon atoms exclusive of esterradicals.

The ring structure of the compounds of the invention is represented bythe following structure:

The exact nature of the steroid moiety is not critical, and it can bederived from any steroid of the general type known to exhibit hormonalor other pharmacological or endocrinologicm properties. Such steroidmoieties have from seventeen to about twenty-three carbon atoms, notcounting carbon content which may be provided by esterified hydroxygroups. Esten'fied hydroxy-steroids are included Within the scope of theinvention, but the carbon content contributed by the acid moiety of theester is not considered part of the essential carbon content of thesteroid.

The steroid moiety can be any member of the estrane, 18-norestrane,androstane, etiocholane, prcgnane or allopregnane series. The foregoingcan contain varying degrees of unsaturation and a variety ofsubstituents in the form of hydrocarbon radicals or functional groupsconventionally employed in me steroid art. Representative of the steroidmoieties which make up the compounds of the invention are those havin atposition 17 a hydroxy, acyloxy, 0x0, or both a hydroxy and a lower-alkylradical, characteristic of the androgenic and anabolic steroids; or alower-alkenyl, lower-alkynyl, acety-l, hydroxyacetyl, 1,2-dihydroxyethyl, l-hydroxyethyl, and the like radicals, characteristic ofthe progestational and adrenal cortical steroids. '1 he steroid moietycan aiso have one or more substituents at other positions of thenucleus, for example, hydroxy, acyloxy, or oxo radicals at positions 1-,4-, 5-, 6-, 7-, 8-, 9-, 11-, 12-, 14-, 15- or 16- (the 0x0 groups beingrestricted to positions having secondary carbons); halogen atoms,pkeferably fluorine, chlorine or bromine, for example at the 1-, 4-, 5-,6-, 7-, 8-, 9-, 11-, 12-, 14-, 15-, 16-, 17- or 21-positions; and one ormore lower-alkyl groups, for example, at the l-, 4-, 5-, 6-, 7-, 8-, 9-,11-, 12-, 14-, 15- or 16-positions. The steroid moiety can also have oneor more double bonds, especially at the 4,5- and/or 6,7-positions. Thesteroid moiety usually possesses angular methyl groups at C and C 3,although 18- and 19-norsteroids and 18,19-bisnorsteroids, lac-king oneor both of the angular methyl groups at C and C respectively, are alsorepresentative steroids.

The 18,19-bisnorsteroid, 18- and 19-norsteroid and natural steroidmoieties in the compounds of the invention contain, respectively,seventeen, eighteen and nineteen carbon atoms plus any carbon contentwhich may be provided by one or more nuclear-1y substituted carboncontaining radicals, up to and including a total of about twenty-threecarbon atoms, exclusive of ester radicals.

Nhen acy-loxy radicals are present in the steroid moiety, or when thearomatic hydroxy group is esterified, the acyl radicals are preferablyderived from carboxylic acids having from one to about ten carbon atoms,conventionally employed in the steroid art, and having a molecularweight less than about 200. Representative of the acyl radicals whichcan be present are loWer-alkanoyl radicals, e.g., formy-l, acetyl,propionyl, butyryl, isooutyryl, caproyl, heptanoyl, octanoyl,tn'methylacetyl, and the like; carboxy-loWer-alkanoyl radicals, e.g.,succinyl (,B-carboxypropionyl); cycloalkyl-loWer-alkanoyl radicals,e.g., fi-cyolopentylpropionyl, fl-cyclohexylpropionyl, and the like;monocarbocyclic aroyl radicals, e.g., benzoyl ptol-uyl, p-nitrobenzoyl,3,4,S-t1irnethyloxybenzoyl, and the like; monocarbocyclicaryl-lower-alkanoyl or -al'kenoyl radicals, such as phenylacetyl,fi-phenylprop-ionyl, cinnamoyl, and the like; and monocarbocyclicaryloxy-loweralkanoyl radicals, such as p-chlorophenoxyacetyl, and thelike. Esters of inorganic acids, for instance, phosphoric acid, are alsocontemplated.

The compounds of the invention are prepared by the following sequence ofreactions:

Hydrol. Q

CODE

OOOH

III IV In the above formulas Q represents the remaining portion of thesteroid moiety described above, and R is a loweralkyl radical havingfrom one to six carbon atoms. A 2-hydroxymethylene-3-oxo steroid (I) iscondensed with a di-loWer-alkyl acetonedicarboxylate to give a3,5-dicarbo lower alkoxy 4' hydroxyi-benzo 1,2:2,3 steroid] (H). T helatter is then hydrolyzed to the corresponding 3,5-dicarboxy compound(HI) and decarboxylated to a 4'-hydroxy[benzo-.1,2:2,3-steroid] (IV).

The condensation between the Z-hydroxyrnethylene-S- 0x0 steroid anddi-loWer-alkyl acetonedicarboxylate is carried out by heatingapproximately equimolar quantities in an inert solvent in the presenceof a strong base, for example, an mkali metal alkoxide, amide orhydride. {The reaction takes place between about 50 C. and C.

The hydrolysis to the dibasic acid III is carried out by heating thediester II with aqueous alkali or aqueous-alcoholic alkali, for example,an aqueous-methanolic solution of potassium hydroxide Thedecarboxylation of the dibasic acid III to produce the phenol IV iscarried out by heating the dibasic acid in the presence of a basicsubstance. The basic substance can be an inorganic base, such assoda-lime or copper oxide, or an organic base such as a high-boilingamine. A preferred basic substance is a high-boiling amine, boilingabove about 150 C., such as quinoline, collidine, and the like.

Compounds in which ring A of the steriod moiety is aromatic (estratrienecompounds) can be prepared by dehydrogenation of the corresponding A-l9-nor-steroids by procedures well-known in other cases to aromatizering A, as by heating with palladium-on-carbon catalyst:

d X e no i wherein R is hydrogen or a lower-alkyl, lower-alkenyl,lower-alkynyl, the acetyl, the hydroxyacetyl, the 1,2-dihydroxyethyl orthe l-hydroxyethyl radical; X is selected from the group consisting of H(ID-(OH) and O; Y and Y represent hydrogen or the methyl radical; and Zrepresents hydrogen or the hydroxy radical, Z being restricted tohydroxy when R represents hydrogen, or a lower-alkyl, lower-alkenyl orlower-alkynyl radical. Another preferred aspect of the inventionincludes compounds difiering from V in having a further double bond inthe 4,5- position (VI), or in both the 4,5-position and the 6,7-position (VII):

VII

The preferred aspects also include carboxylic acid esters of compoundsof structures V, VI and VII. The phenolic hydroxy group, as well as anyfree hydroxy groups attached to the steroid nucleus or on the side chainat C17, can be esterified.

The compounds of Formulas V, VI and VII, being phe 1101s, are acidic innature and form salts upon contacting them with bases, e.g., metalhydroxides, or water-soluble heavy metal salts in aqueous medium.Preferred salts are the alkali metal salts, e.g., sodium or potassiumsalts, although all metal salts are useful as intermediates in the 4;purification of the free phenols. The salts are the equivalent of thefree phenols specifically claimed.

In the above general Formulas V, VI and VII, R, when it represents alower-alkyl, lower-alkenyl, or lower-alkynyl radical, has from one toabout four carbon atoms and may be straight or branched, and thusincludes such groups as methyl, ethyl, propyl, isopropyl, butyl,isobutyl, tertiarybutyl, vinyl, l-propenyl, 2-propenyl, ethynyl,propargyl, and the like.

The compounds of Formulas V, VI and VII are pre-' pared by reacting theappropriate Z-hydroxymethylene- 3-oxo steroid, viz.:

or the corresponding compounds where double bonds are present in the4,5- or the 4,5- and 6,7-positions, with a dilower-alkylacetonedicarboxylate followed by hydrolysis and decarboxylation of theresulting diester. R, X, Z, Y and Y have the same meanings given above.When the steroid moiety contains oxo groups in addition to the one atposition 3, these can be protected as ketal derivatives to preventcompeting reactions. For. example, when compounds in which R representsacetyl or hydroxyacetyl are desired, these radicals can be ketalized byknown methods, e.g., with ethylene glycol, prior to introduction of thehydroxymethylene radical at the 2-position. It has been found, however,that 3,20-dioxo steroids bearing hydroxy groups at the 17- and21-positions can be selectively formylated in the 2-position withoutneed for protecting the ZO-oxo group by ketalization. readily cleaved bydilute acid. An 0x0 group at the 11- position is relatively unreactiveand need not be protected. The ketals are the equivalent of the free oxocompounds specifically claimed.

An alternative method of preparing the 4'-hydroxy- V[benzo-1',2:2,3-steroids] of the invention comprises aromatizing thecorresponding 4-oxo-1,4',5',6'-tetrahydrobenzo compounds, viz.:

/ Ma Q B=N stands for a tertiary-amino radical, for example,dilower-alkylamino, piperidhio, pyrrolidino or morpholino. Tnecondensation takes place by contacting the steroid enamine with methylvinyl ketone in an inert solvent.

The reaction takes place at ordinary temperatures.

A preferred class of 4-oXo-1,4',5',6'-tetrahydrobenzo compounds, usefulas starting materials for preparing 4'-' The ketal groups are wherein Ris lower-alkyl.

The present invention has provided new steroid compounds, namely4-hydroxy[benzo-l,2:2,3-steroids], and these compounds have now beenmade available for study of their endocrinological activities. Compoundsof the invention have indeed been found to possess such activities asset forth below, and they are also useful as intermediates in thepreparation of diiferent species within the scope of the invention byintroduction or" new groups or alteration of groups already present inthe steroid nucleus by known methods. For example, a 4-hydroxy[benzo-1',2:2,3-steroids] having a hydroxy group in the 17-position of thesteroid nucleus (V, VI or VII; R is H, Z is OH) can be oxidized to thecorresponding 17-oxo compound. As another instance, a4'-hydroxy[benzo-1,2':2, 3steroid] having a l-hydroxyethyl radical inthe l7-position (V, VI or VII; R is CH CH(OH)-, Z is H) can be oxidizedto the corresponding 17-acetyl compound (V, VI or VII; R is CH CO, Z isH). Many other alterations of the substituents on the steroid nucleuscan be made by known methods without affecting the fused phenolic ring.-t is also possible by the Birch reduction method (sodium or lithium inliquid ammonia) to convert the aromatic compounds of Formula IV to thehydroaromatic compounds of Formula IX.

Biological evaluation of the 4-hydroxy[benzo-1',2:2, 3-steroids] of theinvention has shown that they possess endocrinological activity. inparticular, they have been found to have estrogenic properties.

The structure of the compounds of the invention was established by themode of synthesis, their ultraviolet and infrared spectra, and by thefact that the values found upon elementary analysis corresponded withthe values calculated for the assigned structures.

The following examples will further illustrate the invention without thelatter being limited thereby.

EXAMPLE 1 Sodium metal (0.51 g., 0.022 mole) was dissolved in 200 ml. ofmethanol, and to this solution there was added 6.36 g. (0.020 mole) ofZ-hydroxymethyleneandrostan- 17,8-ol-3-one and 4.0 g. (0.023 mole) ofdimethyl acetonedicarboxylate. The reaction mixture was refluxed forthree and one-half hours. Thereafter 2 ml. of acetic acid was added, themixture heated to boiling and then cooled in ice. The precipitatedproduct was collected by filtration, recrystallized from methanol anddried at 110 C. in vacuo for eight hours at give 3,5'-dicarbomethoxy-4,17B-dihydroxy[benzo-1',2:2,3-androstane], MP. 204.8 206.2 C. (corr.),[a] =+66.2 (1% in chloroform); ultraviolet maxima at 247 and 320 my.(E=9,600 and 5,300).

In the foregoing procedure it was found possible to employ commercialsodium methoxide instead of preparing it directly from metallic sodium.Likewise, it was found that 86% potassium hydroxide in tertiary-butylalcohol could be used in place of the sodium methoxide.

(b) 3 ',5 -Dicarboxy-4,1 7 B-Dihydroxy [Benzo- J ,2'.2,3-Androstane] Amixture of 11.30 g. of 3',5-dicarbomethoxy-4',17B-dihydroxy[benzo-1,2':2,3-androstane] in the form of its sodium salt, 30g. of potassium hydroxide, ml. of water and 1000 ml. of methyl alcoholwas refluxed with stirring for twenty-three hours. The reaction mixturewas concentrated in vacuo, 800 ml. or" water was added to the residueand the insoluble material removed by filtration. The filtrate wascooled with ice and acidified with concentrated hydrochloric acid,whereupon a gelatinous precipitate formed. The mixture was saturatedwith sodium chloride, extracted twice with ethyl acetate, and theextracts dried over anhydrous sodium sulfate and concentrated to a smallvolume. The product thus obtained was recrystallized from anacetone-n-hexane mixture and dried at C. in vacuo for six hours to give3',5'-dicarboxy- 4',l7fi-dihydroxy[benzo-1',2:2,3-androstane] in theform of rosettes of colorless flattened needles, Ml. above 300 C.(corr.), [a] =+52.5 (1% in pyridine).

(c) 4,17fi-Dihydr0xy [Benzo-I ,2' :2,3-Andr0stane] [V; R is H, X is H Zis OH, Y and Y are CH A mixture of 10 g. o-3,5-dicarboxy-4',17,3-dihydroxy- [benzo-1,2':2,3-androsta-ne] and 60 ml.of quinoline was heated to about 228 C. over a period of about fifteenminutes, and then held at the boiling point (237 C.) for ten minutes.The reaction m xture was cooled to about 50 C. and poured into a mixtureof ice and dilute hydrochloric acid. The precipitate formed wascollected, dissolved in 400 ml. of benzene, and the solution wasconcentrated to a small volume to cause crystallization of the product.The product was recrystallized twice from acetone and dried at 120 C. invacuo for twelve hours to give4,175-dihydroxy[benzo-1',2':2,3-androstane] in the form of colorlessneedles, M.P. 237.8-239.2 C. (corn), [a] =-{46.0 (1% in pyridine);ultraviolet maxima at 283 and 288 mu (E=2,337 and 2,130).

(d) 4 ',1 7,8-Bis( fi-Cyclohexylpropionoxy) [Benze- 1 ',2.'2,3-Andr0stane] A mixture of 2.40 g. of4',17/3-dihydroxy[benzo-1,2':2, 3-androstane], 8.8 g. ofB-cyclohexylpropionio anhydride and 50 ml. of pyridine was held at roomtemperature for about twenty-two hours and then heated on a steam bathfor two and one-quarter hours. The reaction mixture was added to 500 ml.of Water, allowed to stand for one hour and then extracted three timeswith methylene dichloride. The extracts were washed with dilute sulfuricacid and concentrated sodium bicarbonate solution, dried over anhydroussodium sulfate and concentrated to dryness. The residue was dissolved in500 ml. of n-pentane and chromatographed on a column of 200 g. of silicagel. The column was eluted with n-pe-ntane containing-5% ether, and theproduct recrystallized from n-hexane and dried at 90 C. in vacuo forfive hours, to give 4',17fi-bis(13- cyclohexylpropionoxy)[benzo-1,2:2,3-androstane] in the form of colorless needles, -M.P.147.8148.8 C. (corn), [a] =-+29.8 1% in chloroform).

Similarly to the procedure just described, 4',171S-dihydroxy[benzo-1',2'22,3-androstane] can be caused to react with aceticanhydride, propionic anhydride, caproyl chloride, succiric anhydride,B-cyclopentylpropionyl chloride, benzoyl chloride, p-nitrobenzoylchloride, 3,4,5-trimethoxybenzoyl chloride, phenylacetyl chloride,cinnamoyl chloride, or p-chlo'rophenoxy-acetyl chloride, to give,respectively, 4',17;8 diacetoxy[benzo-1',2:2,3-androstane],4',17B-dipropionoxy[benzo-1',2'22,3-androstane] 4',17B- dicaproyloxy[benzo-1',2' 2,3-androstane] 4,17,B-bis(;3- carboxypropionoxy)[benzo-1',2 2,3-androstane] 4',17,8 bis(fl cyclopentylpropionoxy) [benzo1,2':2,3 androstane] 4',17fi-dibenzoyloxy[benzo-1',212,3-androstane],4,l7 8 bis(p-nitrobenzoyloxy) [benzo i1,2:2,3 androstane],4',17,8-bis(3,4,S-trimethoxybenzoyloxy) [benzo-l',

2' 2,3 -androstane] 4', l Zd-bis (phenylacetoxy) [benzo- 12':2,3-androstane], 4', 17/3-dicinnarnoyloxy[benzo-1,2:2, 3-androstane],or 417,8-bis(4-chlorophenoxyacetoxy) [benzo-l ',2' 2,3-androstane]4,17fl-dihydroxy[benzo-1',2:2,3-androstane] is obtained in the form ofits sodium or potassium salts when treated with an aqueous solution ofsodium hydroxide or potassium hydroxide, respectively. 4,17,8-dihydroxy[benzo-l',2:2,3-androstane] is obtained in the form of its copper, zincor lead salts when an aqueous solution of its sodium salt is treatedwith an aqueous solution of cupric chloride, zinc chloride or leadnitrate, respectively.

4-hydroxy-17-oxo[benzo-1,2:2,3-androstane] can be prepared by treating asolution of 4,17p-dihydroxy[benzo- 1,2:2,3-androstane] in glacial aceticacid with a solution of chromic oxide in aqueous acetic acid. Theproduct is isolated by the addition of water and collection of theresulting precipitate.

The compounds of the following examples were prepared according to theprocedures described above in Example I. In some instances the finalproduct was purified by chromatographing it on aluminum oxide andeluting with benzene containing of ether, or with benzene containingincreasing amounts of ethyl acetate.

EXAMPLE 2 (a) Z-hydroxymethylene-17ot-methylandrostan-175-01- 3-one wascondensed with dinethyl acetonedicarboxylate to give3,5'-dicarbomethoxy-4',l7fl-dihydroxy-l7oc-methyl[benzo-'1,2':2,3-androstane], M.P. 236.0l.6 C. (corn) (recrystallizedfrom acetone), =+46.0 (1% in chloroform); ultraviolet maxima at 248 and320 mu (E=9,700 and 5,400).

(b) 3',5-dicarbomethoxy-4',17fi-dihydroxy-17ot-methyl[benzo-1',222,3-androstane] was saponified with potassium hydroxide inmethanol to give 3,5'-dicarboxy-4,17,8-dihydroxy-l7a-'nethyl{henzo-l',2:2,3-androstane], M.P. 209.4-2120 C.(corn) (recrystallized from acetone), [cc] =+35.4- (1% in pyridine).

(c) 3',5-dicarb0xy-4'-l 7fi-dihydroxy-l 7 a-methyl [benzo-1,2:2,3-androstane] was decarboxylated in quinoline to give 4,17B-dihydroxy-17ot-methyl [benzo-1',2 2,3 -androstane] [V; R is CH X isH Z is OH, Y and Y are CH pinkish needles, M.P. 211.0218.4 C. (corn),

(1% in chloroform); ultraviolet maxima at 222, 283 and 288 me (E=7,081,2,334 and 2,124

EXAMPLE 3 (a) 2-hydroxymethylene-17a-methyl-4-androsten-175- ol-3-onewas condensed with dimethyl acetonedicarboxylate to give3,5-dicarbomethoxy-4,l7fi-dihydroxy-l7umethyl[benzo-1',2:2,3-androst-4-ene, colorless prisms, M.P. 238.0247.0C. (dec.) (corr.) (recrystallized from acetone), [a] =15.0 (1% inchloroform); ultraviolet maxima at 223, 292, 302 and 342 111,11(E:17,900, 20,300, 21,000 and 9,900).

(b) 3',5-dicarbornethoxy-4',17,8-dihydroxy-Not-methyl[benzo-1',2':2,3-androst-4-ene] was saponified with potassium hydroxidein methanol to give 3,5'-dicarboxy-4',17B- dihydroxy 17oz methyl[benzo1',2':2,3-androst-4-ene], colorless prisms, M.P. 224.8226.8 C. (dec.)(corn) (recrystallized from acetone), [oc] =+31.2 (1% in pyridine).

(c) 3',5' dicarboxy 4,17B dihydroxy 17a methyl[benzo-1',2':2,3-androst-4-ene] was decarboxylated in quinoline to give4,l7 8-dihydroxy-l7a-methyl[benzo- "'1',2:2,3-androst-4-ene] [VI; R isCH X is H Z is OH, Y and Y are CH pale yellow needles, M.P. 231.1- 241.2C. (corn) (recrystallized from methanol) 1% in chloroform); ultravioletmaxima at 224, 229, 268, 279 and 305 m, (E=25,600, 25,500, 12,100,10,900 and 3,900); infrared maxima at 2.82, 2.97, 3.11, 3.44, 6.11,6.24, 6.34, 6.65-6.68 and 6.90,.

EXAMPLE 4 (a) 2-hydroxymethylene-l7a-methyl-4,-androstadien-17B-ol-3-one was condensed with dimethyl acetonedicarboxylate to give3',5-dicarhornethoxy-4,17fi-dihydroxy- 17 amethyl[benzo-1,2':2,3-androsta-4,6-diene], yellow leaves, M.P.246.4254.2 C. (corn) (recrystallized from acetone), [a] =-35l.6 (1% inchloroform); ultraviolet maxima at 237, 316, 329 and 359 m (E=-13,347,19,600, 21,000 and 15,700).

(b) 3',5-dicarbomethoxy-4',17B-dihydroxy-17u-methyl[benzo-l,2':2,3-androsta-4,6-diene] was saponified with potassiumhydroxide in methanol to give 3',5'-dicarboxy- 4',17B-dihydroxy17u-methyl[benzo-1',2':2,3 androsta- 4,6-diene], M.P. 232234 C. (dec.)(uncorn) (recrystallized from acetone-hexane), [oz] =277 (1% inpyridine).

(c) 3,5'-dicarboxy-4,17,8-dihydroxyl7a-methyl[benzo-1',2':2,3-androsta-4,6-diene] was decarboxylated inquinoline to give 4',l7fl-dihydroxy-17a-methyl[benzo-1',222,3-androsta-4,6-diene] [VII; R is CH X is H Z is OH, Y and Y areCH yellow needles, M.P. 246.4- 254.6 C. (corr.) (recrystallized frommethanol), [a] =l9l (1% in chloroform); ultraviolet maxima at 233, 241,249, 293, 305 and 325 m (E=16,174, 16,835, 15,224, 23,665, 24,385 and11,586).

EXAMPLE 5 (a) 2-hydr0xymethylene-17u-ethynyl-4-androsten-175 ol-3-onewas condensed with dimethyl acetonedicarboxylate to give3',5-dicarhomethoxy-4',17B-dihydroxy-17aethynyl[benzo 1',2':2,3androst-4-ene], M.P. 208.8- 211.6 C. (corn) (recrystallized fromacetone-hexane), [a] :96.2 (1% in chloroform); ultraviolet maxima at223, 292, 302 and 340 m, (E=18,139, 21,208, 21,539 and 9,961).

(b) 3 ',5'-dicarbomethoxy-4',17,8-dihydroxy-17u-ethynyl[benzo-1,2':2,3-androst-4-ene] was saponified with potassium hydroxidein methanol to give 3','5-dicarboxy-4',17 8- dihydroxy17a-ethynyl[benzo-1,2':2,3 androst-4-ene], M.P. 202.4210 C. (dec.)(corn) (recrystallized from methanol), [a] -=101.5 (1% in pyridine).

(c)3,5-dicarboxy-4',17,3-dihydroxy-17a-ethynyl[benzo-1,2':2,3-androst-4-ene]was decarboxylated in quinoandrost-4-en'e] [VI; R is CECH, X is H Z isOH, Y and Y are CH needles, M.P. 238.4240.2 C. (corr.)(recrystallizedfrom methanol), x] =+37.4 (1% in chloroform); ultraviolet maxima at 224,227, 260, 268, 278, 305 and 312 I'll/L (E=25,200, 25,000, 6,800, 11,900,10,700, 3,800 and 3,400). The infrared absorption spectrum showed thepresence of a triple bond at 4.29

EXAMPLE 6 (a) 17,20;20,21bismethylenedioxy-2-hydroxymethylene-4-pregnene-3,11-dione was condensedwith dimethyl acetonedicarboxylate to give 17,20;20,2l-bismethylenedioxy3',5-dicarhomethoxy-4'-hydroxy-11-oxo[benzo- 1',2:2,3-pregn-4-ene], M.P.273.2276.0 C. (corn) (recrystallized from acetone), [a] =+3.6 (1% inchloroform); ultraviolet maxima at 225, 291, 302, 342 and 352 mp.(E=18,000, 20,300, 20,600, 9,L00 and 8,400).

(b) 17,20;20,21 bismethylenedioxy 3',5' dicarbo methoxy 4' hydrox-1l-oxo[benzo-1,2':2,3-pregn-4 one] was saponified with potassiumhydroxide in metha- 1101 to give17,20;20,2l-bismethylenedioxy-3',5T-dicar= boxy 4'hydroxy-l1-oxo[benzo-1,2:2,3-pregn-4-ene],

obtained in the form of a tan colored solid.

(c) 17,20;20,21 bismethylenedioxy 3',5 dicarboxy 4hydroxy-ll-oxo[benZo-1',212,3-pregn-4-ene] V was decarboxylated inquinoline to give 17,20;20,21-bis'- methylenedioxy-4-hydroxy-11-ox0[benzo-l,2' :2,3-pregn- 4-ene], M.P. above 315 C. (recrystallizedfrom benzene r and dimethylformamide), [a] =+70.5 1% in pyridine);ultraviolet maxima at 227, 231, 260, 268, 279, 306 and 318 m (E=26,800,27,500, 880, 12,000, 11,000, 4,400 and 3,500).

(d) 4',l7oc,21 trihydroXy-ll,20-dioxo[benzo-1,2:2,3- pregn-4-ene] [Vl; Ris COCH OH, X is 0, Z is OH, Y and Y are CH was prepared by treating 3.1g. of l7,20;20,21 bismethylenedioxy-4-hydroxy-11-oxo[benzo-l,2':2,3-pregn-4-ene] with 100 ml. of acetic acid and ml. of 60%perchloric acid. After stirring the mixture for three days at roomtemperature, it was added to 500 ml. of water and partly neutralizedwith sodium carbonate. The mixture was filtered to give about 3 g. ofsolid product.

EXAMPLE 7 (a) 2 hydroxymethylene-4-pregnen-20-ol-3-one was condensedwith dimethyl acetonedicarboxylate to give 3',5dicarbomethoxy-4,20;3-dihydroxy[benzo-1,2:2,3- pregn-4-ene], M.P.177.8180.2 C. (corn) when recrystallized from benzene, [a] 5=-13.1 (1%in chloroform); ultraviolet maxima at 222, 291, 302 and 340 mu(E=17,000, 19,400, 20,100 and 9,500).

(b) 3,5 dicarbomethoxy 4,20fi-dihydroxy[benzo- 1,2:2,3-pregn-4-ene] wassaponified with sodium hydroxide in methanol to give3,5-dicarboxy-4,20fi-dihy droXy[benzo-1',2:2,3-pregn-4-ene], M.P.185-225" C., which was decarboxylated without further purification.

(c) 3',5 dicarboXy-4,20B-dihydroxy[benzo-l,2:2, 3-pregn-4-ene] wasdecarboxylated in quinoline to give4,20;8-dihydroxy[benZo-1,2:2,3-pregn-4-ene] [Vl; R is CH(OH)CH X is H Zis H, Y and Y are CH M.P. 208.8210.2 C. (corn) when recrystallized frombenzene, [a] =+113.3; ultraviolet maxima at 224, 229, 260, 268, 279, 304and 311 mu (E=24,600, 24,400 8,450, 11,600, 10,500, 3,900 and 3,390).

EXAMPLE 8 (a) 2 hydroxymethylene-4-pregnene-3,20-dione ethylene glycolketal was condensed with dimethyl acetonedicarboxylate to give3',5'-dicarbomethoXy-4-hydroxy 20-oXo[benzo-1,2:2,3-pregn-4-ene]20-ethylene glycol ketal, M.P. 203204.8 C. (corn) (recrystallized frombenzene), [a] =+32.3 (1% in chloroform); ultraviolet maxima at 223, 291,302 and 340 my. (E=20,900, 21,800, 22,400 and 10,500).

(5) 3,5 dicarbomethoxy-4-hydroXy-20-oXo[benzo- 1',2:2,3-pregn-4-ene]20-ethylene glycol ketal was saponified with sodium hydroxide inmethanol to give 3,5 dicarboxy 4 hydroXy-20-oXo[benZo-l,2:2,3-pregn-4-ene] ZO-ethylene glycol ketal, M.P. 160-175 C. (oncorr.) (dec.).

(c) 3',5' dicarboxy-4'-hydroxy-20-oxo[benzo-1',2:2, 3-pregn-4-ene]20-ethylene glycol ketal was decarboxylated in quinoline to give4'-hydroxy-20-oxo{benzo- 1,2:2,3-pregn-4-ene] ZO-ethylene glycol ketal.This latter was dissolved in acetic acid and pyridine containing alittle water, the solution concentrated on a hot plate, and the solidmaterial which separated was recrystallized from pyridine to give4-hydroXy-20-oxo [benzo-1,2:2,3-pregn-4-ene] [V1, R is COCH X is H Z isH, Y and ,Y are CH M.P. 303314 C. (uncorr.).

The following, compounds can be prepared by the procedure describedabove in Example 1:

4,l75 dihydroXy[benzo-l,2:2,3-androst-4-ene] [VI; R is H, X is H Z isOH, Y and Y are CH by condensing 2hydroxymethylene-4-androsten-17fl-ol-3-one with dimethylacetonedicarboxylate, followed by saponifying and decarboxylating theintermediate 3,5-dicarbornethoxy compound.

4,17B dihydroxy-l7ct-ethyl[benzo-1,2:2,3-androst-4- ene] [VI; R is C H Xis H Z is OH, Y and Y are CH by condensing2-hydroxymethylene-17a-ethyl-4- androsten-17B-ol-3-one with dimethylacetonedicarbox- 10 ylate, followed by sa'ponifying and decarboxylatingthe intermediate 3',5'-dicarbomethoxy compound.

4,17;3 dihydroxy-17 a-vinyl [benzo-1,2:2,3-androst-4- ene] [VI; R isCH=CH X is H Z is OH, Y and Y are CH by condensing2-hydroxymethylene-17a-vinyl- 4-androsten-17B-ol-3-one with dimethylacetonedicarboxylate, followed by saponifying and decarboxylating theintermediate 3',5-dicarbomethoxy compound.

4, 17,8 dihydroxy-17a-methy1 [benzo-1,2' 2,3-etiocholane] [V; R is CH Xis H Z is OH, Y and Y are CH (rings A/B cis)], by condensingZ-hydroxymethylene 17u-methyletiocholan-l7fl-ol-3-one with dimethylacetonedicarboxylate, followed by saponifying and decarboxylating theintermediate 3',5 dicarbomethoxy compound.

4,17,8 dihydroxy-lh-methyl[benzo-l,212,3-19-norandrostane] [V; R is CH Xis H Z is OH, Y is H, Y is CH by condensing2-hydroxymethylene-l7ameththyl 19-norandrostan-17,8-ol-3-one withdimethyl acetonedicarboxylate, followed by saponi-fying anddecarboxylating the intermediate 3,5-dicarbomethoxy compound.

4,17fi dihydroxy 17a-ethyl[benzo-1,2:2,3-androstane] [V; R is C H X is HZ is OH, Y and Y are CH by condensing17a-ethyl-Z-hydroxymethyleneandrostan-l7fi-ol-3-one with dimethylacetonedicarboxylate, followed by saponifying and decarboxylating theintermediate 3,5-dicarbomethoxy compound.

4 hydroxy-ZO-oxo[benzo-l,2:2,3-al'lopregnane] [V; R is COCH X is H Z isH, Y and Y are CH (rings A/ B trans) by condensingZ-hydroxymethyleneallopregmane-3,20-dione 20-ethylene glycol ketal withdimethyl acetonedicarboxylate, followed by saponifying anddecarbonylating the intermediate 3,5-dicarbomethoxy compound, andheating the resulting product with dilute acetic acid to cleave theketal group.

4' hydroxy-ZO-oxo[benzo-1,2':2,3-pregnane] [V; R is COCH X is H Z is H,Y and Y are CH (rings A/ B cis)], by condensing2-hydroxymethylenepregnane- 3,20-dione 20-ethylene glycol ketal withdimethyl acetonedicarboxylate, followed by saponifying anddecarboxylating the intermediate 3,5'-dicarbomethoxy compound, andheating the resulting product with dilute acetic acid to cleave theketal group.

4,17B dihydroXy[benzo-1,2':2,3-androsta-4,6-diene] [VIL R is H, X is H Zis OH, Y and Y are CH by condensing2-hydroxymethylene-4,6-androstadien-17B-ol- 3-one with dimethylacetonedicarboxylate, followed by saponifying and decarboxylating theintermediate 3,5- dicarbomethoxy compound.

4,17fi dihydroxy 17a-ethyl[benzo-1,2':2,3-androsta 4,6-diene] [VII; R isC H X is H Z is OH, Y and Y are CH by condensing2-hydroxymethylene-17u-ethyl- 4,6-androstadien-17,8-ol-3-one withdimethyl acetonedicarboxylate, followed by saponifying anddecarboxylating the intermediate 3,5-dicarbomethoxy compound.

4,17,8 dinydroxy 4,4,170c trimethyl[benzo-l,2:2,3-17a-trirnethyl-S-androsten-17B-ol-3-one with dimethylacetonedicarboxylate, followed by saponifying and decarboxylating theintermediate 3,5-dicarbornethoxy compound.

4,17B dihydroxy 4,4 dimethyl[benzo 1,2:2,3- androst-S-ene], bycondensing 2-hydroXymethylene-4,4-dimethyl-S-androsten-17p-ol-3-one withdimethyl acetonedicarboxylate, followed by saponifying anddecarboxylating the intermediate3, -..-.icarbomethoxy compound.

4,17,8 dihydroxy 4,4,l7a trimethyl[benzo-l',2:2,3- androstane], bycondensing 2-hydroxyrnethylene-4,4,17o:-trimethylandrostan-17fi-ol-3-one with dimethyl acetonedicarboxylate,followed by saponifying and decarboxylating the intermediate3,5-dicarbomethoxy compound.

4,17B dihydroxy 6a,].7oa dimethyl[benzo-1,2:2,3- androst-4-ene], bycondensing 2-hydroxyrnethylene-6a, 17a-dimethyl-4-androsten-l7,6-01 3one with dimethyl acetonedicarboxylate, followed by saponifying and deli 'carboxylating the intermediate 3,5'-dicarbomethoxy compound.4,l75-dihydroxy 17oz ethynyl[benzo-1,2:2,3-androstane] [V; R is CECE, Xis H Z is OH, Y and Y are CH by condensingZ-hydroxyrnethylene-l7u-ethnyl- *androstan-175-ol-3-one with dimethylacetonedicarboxylate, followed by saponifying and decarboxylating theintermediate 3',5'-dicarbomethoxy compound.

4',l75 dinydroxy 17a propargyl{benZ-1',2:2,3- 'androstane] [V; R isCHZCECH, X is H Z is CH, Y and -Y are CH by condensingZ-hydroXymethylene-Uupropargylandrostan-175-ol-3-one with dimethylacetonedicarboxylate, followed by saponifying and decarboxylating theintermediate 3,5'-dicarbomethoxy compound.

4',20,21 trihydroxy[benzo-1',2'12,3-pregn-4-ene] [VI; R is CH(OH)CH OH,X is H Z is H, Y and Y are CH by condensing2-hydroxyrnethylene-4-pregnene-20, 2l-diol-3-one with dimethylacetonedicarboxylate, followed by saponifying and decarboxylating theintermediate 3,5'- dicarbomethoxy compound.

9 fiuoro 4,1 l5,17a,21 tetrahydroxy 20-oXo[benzo- 1,2':2,3-pregn-4-ene],by condensing Z-hydroxymethylene-9-fiuoro-4-pregnene-115,17a,21-triol3,20 dione 20- monoethylene glycol ketal with dimethylacetonedicarboxylate, followed by saponifying and decarboxylating theintermediate 3,5'-dicarbomethoxy compound, and heating the resultingproduct with dilute acetic acid to cleave the ketal group.

4,16a,17ct,21 tetrahydroxy 20 0X0 95,115 oXido-[benzol,2':2,3-pregn-4-ene], by condensingZ-hydroxymethylene-4-pregnene-l6tt,17 ,21 triol 3,20 dione 95, 115-oXide20-monoethylene glycol ketal with dimethyl acetonedicarboxylate,followed by saponifying and decarboxylating the intermediate3',S-dicarbomethoxy compound, and heating the resulting product withdilute acetic acid to cleave the ketal group.

4,175 dihydroxy 17a propynyl 6 methyl [benze- 1',2':2,3-androst-4-ene],by condensingZ-hydroxymethylene-17a-propynyl-fi-methyll-androsten-175-ol-3-one withdimethyl acetonedicarboxylate, followed by saponifying anddecarboxylating the intermediate 3,5-dicarbomethoxy compound.

4,l 15,l7c:,21 tetrahydroxy 2Q oxo[benzo l',2':2,3 pregn-4-ene] [Vl; Ris COCH OH, X is (H) (OH), Z is OH, Y and Y are CH by condensing2-hydroxymethylene-4-pregnene-1 15,17a,21-triol-3,20-dione20-monoethylene glycol ketal with dimethyl acetonedicarboxylate,followed by saponifying and decarboxylating the intermediate3',5-dicarbomethoxy compound, and heating the resulting product withdilute acetic acid to cleave the ketal group.

4',17cc,21 trihydroxy 11,20 dioxo['oenzo 1',2':2,3- pregna-4,6-diene][VII; R is COCH OH, X is 0, Z is OH, Y and Y are CH by condensing2-hydroxymethylene- 4,6-pregnadiene-17,21-di0l-3, 1 1,20-trione20-monoethylene glycol ketal with dimethyl acetonedicarboxylate,followed by saponifying and decarboxylating the intermediate3',5-dicarbomethoxy compound, and heating the resulting product withdilute acetic acid to cleave the ketal group.

4',17a,2l trihydroxy 20 oxo[benzo 1',2':2,3- pregn-4-ene] [VL R is COCHOH, X is H Z is OH, Y and Y are CH by condensing 2-hydroxymethylene-4-pregnene-17u,21-diol-3,20-dione 2(l-monoethylene glycol ketal .withdimethyl acctonedicarboxylate, followed by saponifying anddecarboxylating the intermediate 3',5- dicarbomethoxy compound, andheating the resulting product with dilute acetic acid to cleave theketal group.

4',17a,2l trihydroxy 11,20 dioxo 6 methyl [benzo-1',2':2,3-pregn-4-ene], by condensing 2-hydroxymethylene 6 methyl 4pregnene 17Ct,21 diol 3,11,20- trione 20-n1onoethylene glycol ketal withdimethyl acetonedicarboxylate, followed by saponifying anddecarooxylating the intermediate 3,5-dicarbomethoxy compound, andheating the resulting product with dilute acetic acid to cleave theketal group.

4,17C,21 uihydroxy 11,20 dioxo 9 fluoro 6-methyl-[benzo-1,2:2,3-pregn-4-ene], by condensing 2- hydroxymethylene 9fiuoro 6 methyl 4 pregnene- 17a,21-diol-3,11,20trione 2tl-monoethyleneglycol ketal with dimethyl acetonedicarboxylate, followed by saponifyingmd decarboxylating the intermediate 3',S'-dicarbo methoxy compound, andheating the resulting product with dilute acetic acid to cleave theketal group.

4',115,16e,17a,21 pentahydroxy 20 ox0[benzo- 1,2':2,3-pregn-4-ene], bycondensing 2-hydroxymethylene 4 pregnene llfl,l6a,l7a,21 tetrol 3,20dione 20-monoethylene glycol ketal with dimethyl acetonedicarboxylate,followed by saponifying and decarboxylating the intermediate3,5'-dicarbomethoxy compound, and

heating the resulting product with dilute acetic acid to' cleave theketal group.

4',l6cz,l7cc 21 tetrahydroxy 11,20 dioxo[benzo- 1,2':2,3-pregn-4-ene],by condensing Z-hydroxyrnethylene 4 pregnene 16a,170t,21 triol 3,11,20trione 20- monoethylene glycol ketal with dimethyl acetonedicarboxylate,followed by saponifying and decarboxylating the intermediate3,5-dicarbomethoxy compound, and heating the resulting product withdilute acetic acidto cleave the ketal group.

4',115,21 trihydroxy[benzo 1,2:2,3 pregna 4, 17(20)-diene], bycondensing 2-hydroxymethylene-4,

17(20)-pregnadiene-l15,21-diol-3-one with dimethylacetonedicarboxylate,followed by saponifying and decarboxylating the intermediate3,5-dicarbomethoxy compound.

4,65,175 trihydroxy[benzo 1',2':2,3 androstane], by condensing 2hydroxymethyleneandrostane 65,175-

diol-3-one with dimethyl acetonedicarboxylate, followedacetonedicarboxylate, followed by saponifying decarboxyl- V ating theintermediate 3',5-dicarbomethoxy compound.

4',175 dihydroxy 11 oxo[benzo 1',2':2,3 androst- 4-ene] [VI; R is H, Xis 0, Z is OH, Y and Y are CH by condensing2-hydroxymethylene-4-androsten- 175-ol-3,11-dione with dimethylacetonedicarboxylate, followed by saponifying and decarboxylating theintermediate 3,'5-dicarbomethoxy compound.

4',65,l75 trihydroxy[benzo 1,2':2,3 androst 45 ene], by condensingZ-hydroxymethylene-4-androstene- 65,175-diol-3-one with dimethylacetonedicarboxylate, followed by saponifying and decarboxylating theinter. mediate 3,5-dicarbomethoxy compound.

4,65,175 trihydroxy 17a methyl[benzo 1,2':2,3- androst-4-ene], bycondensing 2-hydroxymethylene-17 an1ethyl-4-androstene-65,175-diol-3-0newith dimethyl acetonedicarboxylate, followed by saponifying anddBCZIIlJOX- ylating the intermediate 3',5'-dicarbomethoxy compound.

4',14a,175 trihydroxy[benzo 1',2':2,3 androst-4- ene], by condensingZ-hydroxyrnethylene-4-androstene 14a,l75-diol-3-one with dimethylacetonedicarboxylate, followed by saponifying and decarooxylating theintermediate 3,5'-dicarbomethoxy compound. 7 V

4',175 dihydroxy methyl[benzo 1',2':2,3- androst-4-ene], by condensing2-hydroxyrnethylene-165- methyl-4-androsten-l75-ol-3-one With dimethylacetonedicarboxylate, followed by sapenifying and decarboxylating theintermediate 3',5-dicarbornethoxy compound.

4',11o:,l7[3 trihydroxy[benzo 1',2:2,3 androst 4- one] [VI; R is H, X is(H) (OH), Z is OH, Y and Y are CH by condensingZ-hydroxymethylenel-androstene-11a,17fi-diol-3-one with dimethylacetonedicarboxylate, followed by saponifying and decarboxylating theintermediate 3',5-dicarbomethoxy compound.

4,65,17;3 trihydroxy[benzo 1',2:2,3 19 norandrost-4-ene], by condensingZ-hydroxymethylene-l9-nor- 4-androstene-6,8,17fi-diol-3-one withdimethyl acetonedicarboxylate, followed by saponilying anddecarboxylating the intermediate 3',5'-dicarbomethoxy compound.

4,17;5' dihydroxy 4 methyl[benzo 1,2':2,3 androst-4-ene], by condensing2-hydroXymethylene-4-methyl-4-androsten-l7fi-ol-3one with dimethylacetonedicarboxylate, followed by saponifying decarboxylating theintermediate 3,5'-dicarbornethoxy compound.

4',17[3 dihydroxy 4,17a dimethyl[benzo 1,2':2,3- androsti-ene], bycondensing Z-hydroxymethylenel,17adimethyl4-androsten-17,8-ol-3-one withdirnethyl acetone- .dicarboxylate, followed by saponifying anddecarboxylating the intermediate 3,5'-dicarbomethoxy compound.

4',17;3 dihydroxy 17a ethynyl[benzo 1,2':2,3- androsta-4,6-diene] [VII;R is CECH, X is 1-1 Z is OH, Y and Y are CH by condensingZ-hydroxymethylenel7a-ethynyl-4,6-androstadien-l7B-ol-3-one withdimethyl acetonedicarboxylate, followed by saponifying anddecarboxylating the intermediate 3',5-dicarbometh0xy compound.

4,6,8,l7ot,21 tetrahydroxy 2O oxo[benzo 1,2':2,3- allopregnane], bycondensing Z-hydroxymethyleneallopregnane 6B,l7a,21 triol 3,20 dione 2Omonoethylene glycol ketal with dimethyl acetonedicarboxylate, followedby saponifying and decarboxylating the intermediate 3,5'-dicarbornethoxycompound, and heating the resulting product with dilute acetic acid tocleave the ketal group.

4',l2oc,17a,2l tetrahydroxy 2O oxo[benzo 1,2':2, S-pregnl-ene], bycondensing Z-hydroxymethylene-lpregnene 12a,l7c,21 triol 3,20 dione 2Omonoethylene glycol hotel with dimethyl acetonedicarboxylate, followedby saponifying and decarboxylating the intermediate 3',5-dicarbomethoxycompound, and heating the resulting product with dilute acetic acid tocleave the ketfl group.

4 ,l7a,21 trihydrox l2,2O dioxo[benzo l',2':2,3- allopregnane], bycondensing Z-hydroxymethyleneallopre nane 17u,2l diol 3,12,26 trione 2Omonoethylene glycol ltetal witn dimetnyl acetonedicarboxylatc, followedby saponifying and decarboxylating the intermediate 3',5-dicarbomethoxycompound, and heating the resulting product with dilute acetic acid tocleave the ketal group.

4' hydroxy 2O oxo[benzo 1',2:2,3 pregna 4,11- diene], by condensing2-hydroxymethylene-4,1l-pregnadiene-3,20-dione 20-monoethylene glycolketal with dimethyl acetonedicarboxylate, followed by saponifying anddecarboxylating the intermediate 3,5'-dicarbomethoxy compound, andheating the resulting product with dilute acetic acid to cleave theketal group.

4',l7a dihydroxy 20 oxo[benzo 1',2:2,3 pregn- 4-ene] [VL R is COCH X isH Z is OH, Y and Y are CH by condensingZ-hydroxyrnethylenel-prewenl7at-ol-3,20-dione 29''nonoethylene glycolketal with diniethyl acetonedicarboxylate, followed by saponifying anddecarboxylating the intermediate 3',5'-dicarbomethoxy compound, andheating the resulting product with dilute acetic acid to cleave thekctal group.

4 hydroxy 17cc methyl 20 oxo[benzo 1',2:2,3 pregni-ene], by condensingZ-hydronyrnethylene-17amethyl 4 pregn'ene 3,20 dione 20 monoethyleneglycol hetal with dimethyl acetonedicarboxylate, follower by saponifyingand decarboxylating the intermediate 3',5'-dicarbornethoxy compound, andheating the resulting product with dilute acetic acid to cleave thelietal group.

1% by condensin Z-hydroxymethylenel-pregnen-6fi-ol-3,20- dioneZQ-rnonoethylene glycol ketal with dimethyl acetonedicarboxylate,followed by saponifying and decarboxylating the intermediate3,5-dicarbomethoxy compound, and heating the resulting product withdilute acetic acid to cleave the ketal group.

4',7,8,11,8-trihydroxy 2O oXo[benzo-i,2':2,3-pregn- 4-ene], bycondensing 2 l1ydroxyrnethylene-4-pregnene- 75,11 ,B-diol-3,20-dione20-monoethylene glycol ketal with dimethyl acetonedicarboxylate,followed by saponifying and dccarboxylating the intermediate3,5-dicarbomethoxy compound, and heating the resulting product withdilute acetic acid to cleave the ketal group.

4',17a,21-trihydroxy 12:4 chloro-l1,20-dioxo[benzo-1,2:2,3-pregn-4-ene], by condensingZ-hydroxymethylone-12a-chloro-4-pregnene-l7afi1-diol-3,11,20-trione 20-monoeth lene glycol ketal with dimethyl acetonedicarboxylate, followedby saponifying and decarboxylating the intermediate 3,5'-dicarbomethoxycompound, and heating the resulting product with dilute acetic acid tocleave the ketal group.

4-hydroxy 20 oxo[benzo 1,2':2,3 18,19 bisnorpregn-Lene] [VI; R is COCH Xis H Z is H, Y and Y are H], by condensing Z-hydrQXym-ethyIene-I8,19-bisnor-4-pregnene-3,ZO-dione 20-monoethylene glycol etal with dimethylacetonedicarboxylate, followed by saponifying and decarboxylatlng theintermediate 3,5'- dicarbomethoxy compound, and heating the resultingproduct with dilute acetic acid to cleave the ketal group.

4,7u,l2a-trihydroxy 20 0X0[benzo-l,2:2,3-pregn-4- one], by condensing2-hydroxymethylene-4-pregnene- 7a,l2oc-di0l-3,2Q-fll0fi6ZG-ntonoethylene glycol ketal with dimethyl acetonedicarbozylate,followed by saponifying and decarboxylating the intermediate3',5-dicarbomethoxy compound, and heating the resulting product withdilute acetic acid to cleave the ketal group.

4-hydroxy 7,20 dioxo [benzo-1,2:2,3-allopregnanc] by condensing2-hydroxymeth leneallopregnane-3,7,20- trione 7,20-bis-(ethylene glycolketal) with dimethyl acetonedicarboxylate, followed by saponifying anddecarboxylating the intermediate 3,5'-dicarbornethoxy compound, andheating the resulting product with dilute acetic acid to cleave theketal group.

4-,17B-dihydroxy 62,170t dimethyl[benzo-1',2':2,3- androstan bycondensing Z-hydroxymethylene-Ga,17adimethylandrostan-l7,8-ol-3-one withdimethyl acetonedicarboxylate, followed by saponifying anddecarboxylating the intermediate 3',5-dicarbomethoxy compound.

4,17fi dihydroxy-lh-propyl[benzo-1',2':2,3-androst- 4-ene] [VI; R is(CI-l CH X is H Z is OH, Y and Y are CH by condensingZ-hydroxymethylene-lhpropyl-4-androsten-17,6-0l-3-one with dimethylacetonedicarbon late, followed by saponifying and decarboxylating theintermediate 3',5-dicarbometl1oxy compound.

4',l7fl-dihydroxy 17a allyl[benzo-l,2:2,3-androst 4-ene] [Vlg R is CHCH=CH X is H Z is OH, Y and Y are CH by condensing2-hydroxymethylene-l7eallyl-4-androsten-17,8-ol-3-one with dimethylacetonedicarboxylate, followed by saponifying and decarboxylating theintermediate 3',5-dicarbomethoxy compound.

4,17B dihydroxy 17c: propargyl[benzo 1',2': ,3- androstr-ene] [V1, is CHCECH, X is H Z is OH, Y and Y are CH by condensing Z-hydrQXymethylene-Uwpropargyl--4-androsten-l7fi-ol-3-one with diniethylacetonedicarboxylate, followed by saponifying and decarboxylating theintermediate 3',5'-dicarbomethoxy compound.

4 ,175 dihydroxy 17a propynyl[benzo l,2:2,3- androst-4-ene] [VL R isCECCH X is H Z is 01-1, Y and Y are CH by condensingZ-hydroxymethylene-17apropynyl-4-androsten-l7B-ol-3-one with dimethylacetonedicarboxylate, followed by saponifying and decarboxylating theintermediate 3',5'-dicarbornethoxy compound.

4',17,B-dihydroxy 17a propyl{benzo-1,2'22,3-androstane] [V; R is CH CHCH X is H Z is OH, Y and Y are CH by condensing2-hydroxyrnethylene-l7ocpropylandrostan-l7fi-ol-3-one with dimethylacetonedicarboxylate, followed by saponifying and decarboxylating theintermediate 3',5-dicarbomethoxy compound.

4',l7,8-dihydroxy 17a methyl[benzo-l',2:2,3-l9-norandrost-4-ene] [V2 Ris CH X is H Z is OH, Y is H, Y is CH by condensingZ-hydroxymethylene-lhmethyl-l9-nor-4-androsten-l7fi-ol-3-one withdimethyl acetonedicarboxylate, followed by saponifying anddecarboxylating the intermediate 3',5-dicarbomethoxy compound.

4',l7fi dihydroxy 17a propynyl[benzo l,2:2,3- androstane] [V; R is CECCHX is H Z is OH, Y and Y are CH by condensingZ-hydroxymethylene-17apropynylandrostan-l7,3-ol-3-0ne with dimethylacetonedicarboxylate, followed by saponifying and decarboxylating theintermediate 3',5-dicarbomethoxy compound.

4,ll,8,l7a,2l-tetrahydroxy 90c fluoro-20-oxo[benzol',2:2,3-pregn-4-ene],by condensing Z-hydroxymethylene-l7,20;20,2l-bismethylenedioxy 90cfluoro-4-pregnen-llfl-ol-3-one with dimethyl acetonedicarboxylate,followed by sapom'fying and decarboxylating the intermediate3,5'-dicarbomethoxy compound, and treating the resulting product withperchloric acid in acetic acid to cleave the bismethylenedioxy group.

4',l1,B,l7a,2l-tetrahydroxy 20 oxo[benzo-l,2:2,3- pregn-4-ene] [VI; R isCOCH OH, X is (H) (OH), Z is OH, Y and Y are CH by condensingZ-hydroxymethylene-l7,20;20,2l-bis-methylenedioxy 4 pregnen-llfi-ol-3-on with dimethyl acetonedicarboxylate, followed by saponifying anddecarboxylating the intermediate 3,5- dicarbomethoxy compound, andtreating the resulting product with perchloric acid in acetic acid tocleave the bismethylenedioxy group.

4'-hydroxy 4,4 dimethyl 20 oxo[benzo-l',2':2,3- pregn-S-ene], bycondensing 2-hydroxymethylene-4,4-dimethyl-pregn-5-ene-3,20-dione20-monoethylene glycol ketal with dimethyl acetonedicarboxylate,followed by saponifying and decarboxylating the intermediate3',5'-dicarbomethoxy compound, and heating the resulting product withdilute acetic acid to cleave the ketal group.

4-hydroxy-6a-r"luoro 20 x0[benzo-l,2:2,3-pregn- 4-ene], by condensing2-hydroxymethylene-6oz-fiuoro-4- pregnene-3,20-dione 20-monoethyleneglycol ketal with dimethyl acetonedicarboxylate, followed by saponifyingand decarboxylating the intermediate 3,5'-dicarbomethoxy compound, andheating the resulting product with dilute acetic acid to cleave theketal group.

4',l7,6 dihydroxy 17a methyl[benzo 1',2:2,3 l9- norandrosta-4,9-diene],by condensing 2-hydroxymethylene 17 methyl 19 nor 4,9 androstadien 17 8ol-3-one with dimethyl acetonedicarboxylate, followed by saponifying anddecarboxylating the intermediate 3,5- dicarbomethoxy compound.

4,17B dihydroxy 7fi,l7a-dimethyl [benzo 1,2:2, 3-androst-4-ene], bycondensing 2-hydroxymethylenefifi,l7oz-dimethyl-4-androsten-17,B-ol-3-one with dimethylacetonedicarboxylate, followed by saponifying and decarboxylating theintermediate 3,5-dicarbomethoxy compound.

4',11B,17oc,21 tetrahydroxy methyl[benzo 1, 2':2,3-pregnane], bycondensing 2-hydroxymethylene-5- methyl 17a,20;20,21bismethylenedioxypregnan 11,8 ol-3-one with dimethylacetonedicarboxylate, followed by saponify'ing and decarboxylating theintermediate 3',5'- dicarbomethoxy compound.

4',9a,17;8 trihydroxy[benzo 1',2':2,3 androstane], by condensing2-hydroxymethylene-9a,17,8-dihydroxyandrostan-3-one with dimethylacetonedicarboxylate, followed by saponifying and decarboxylating theintermediate 3,5-dicarbomethoxy compound.

4',1l 3,17oc,2l tetrahydroxy 66,9a difiuorooxo[benzo-l',2'22,3-pregn-4-ene], by condensing 2-hydroxymethylene17,20;2-0.21 bismethylenedioxy 6,8, 9a-difiuoro-4-pregnen-llfi-ol-3-onewith dimethyl acetonedicarboxylate, followed by saponifying and decar-16 boxylating the intermediate 3,5-dicarbomethoxy compound, and treatingthe resulting product with perchloric acid in acetic acid to cleave thebismethylenedioxy group.

Also within the purview of the invention are benzo derivatives ofD-homosteroids. The following such compounds can be prepared byprocedures analogous to those described hereinabove:

4',17,8 dihydroxy 17oz methyl[benzo 1,2':2,3 D-homoandrostane], bycondensing Z-hydroxymethylene- 17a-methyl-D-homoandrostan-l7f3-ol-3-onewith dimethyl acetonedicarboxylate, followed by saponifying anddecarboxylating the intermediate 3,5-dica rbomethoxy compound.

4',l7fl dihydroxy[benzo l,2:2,3 D homoan drost-4-ene], by condensingZ-hydrOXymethyIene-D- homo-4-androsten-l7/3-ol-3-one with dimethylacetonedicarboxylate, followed by saponifying and decarboxylating theintermediate 3',5-dicarbomethoxy compound.

4',17;8 dihydroxy 17cc methyl[benzo 1',2':2,3'- estra-1,3,5-triene] canbe prepared by heating 4,l7fidihydroxy 17a methyl[benzo l',2':2,3 19 nor4 androstene] with palladium catalyst.

EXAMPLE 9 [X; R is CH A mixture of 15.23 g. (0.05 mole) ofl7u-methylandrostan-l7fi-ol-3-one, 14.2 g. (0.20 mole) of pyrrolidineand 250 ml. of benzene was refluxed under a water separator until 1.3ml. of Water had been collected. The reaction mixture was concentratedin vacuo under nitrogen, ml. of dioxane added to the residue and themixture again concentrated. The residue was dissolved in 100 ml. ofdioxane, placed in a nitrogen atmosphere, and there was added 7.00 g.(0.1 mole) of methyl vinyl ketone in 100 ml. of dioxane over a period ofone-half hour. The mixture was kept at room temperature for two daysunder nitrogen and then concentrated to dryness in vacuo. To the residuewas added 250 ml. of methanol, 40 g. of sodium acetate, 50 ml. of waterand 40 ml. of acetic acid, and the mixture was refluxed for four hoursunder nitrogen and concentrated in vacuo. The residue was extracted withtwo 200 ml. portions of methylene dichloride, and the extracts werewashed with 100 ml. of water, 100 ml. of saturated sodium bicarbonatesolution, 100 ml. of water and 100 ml. of sodium chloride solution,dried over anhydrous sodium sulfate, filtered and concentrated. Achromatographic column was prepared from 500 g. of silica gel, and thecrude product was added as a slurry in a solvent mixture containing 30%methylene dichloride, 20% ether and 50% pentane. The column was elutedwith the same solvent mixture and then with a solvent mixture containing30% pentane brought out the product which was recrystallized.

twice from ethyl acetate and dried for fifteen hours at 75 C. in vacuoto give 17u-methyl-17B-hydroxy-4-oxo-14,5,6'-tetrahydro[benzo-1',2:2,3-androstane] ultraviolet maximum at 242m E:16,700); infrared maxima at 2.94, 6.05 and 6.22m.

in the form of colorless plates, Ml. 190.4-192.8 C. (corn);

([2) 17oz methyl 17B hydroxy 4' X0 1',4',5,6'-tetrahydro[benzo-1',3:2,3-androstane] can be aromatized by heating withpalladium catalyst to give 4',17,8- dihydroxy-lh-methyl [benzo-l ',2'2,3-androstane] identical with the compound obtained above in Example 2,part (c).

I claim:

1. A 4'-hydr0Xy[benzo-l',2:2,3-steroid], the steroid moiety having fromseventeen to about twenty-three carbon atoms exclusive of ester radicalsand being selected from the group consisting of members of the estrane,18-norestrane, androstane, etiocholane, pregnane and allopregnaneseries.

2. A compound selected from the group consisting of (A) compounds havingthe formula wherein R is a member of the group consisting of hydrogen,lower-alkyl, loWer-alkenyl, lower-alkynyl, acetyl, hydroxyacetyl,1,2-dihydroxyethyl and l-hydroxyethyl; X is a member of the groupconsisting of H (H) (OH) and O; Y and Y are members of the groupconsisting of hydrogen and methyl; and Z is a member of the groupconsisting of hydrogen and hydroxy, Z being restricted to hydroxy when Ris a member of the group consisting of hydrogen, lower-alkyl,lower-alkenyl and lower-alkynyl; (B) compounds of the above formulahaving a double bond in the 4,5-position; (C) compounds of the aboveformula having two double bonds, one in the 4,5- position and the otherin the 6,7-position; and (D) carboxylic acid esters of (A), (B) md (C),the acyl moieties of said esters having from one to ten carbon atoms andhaving a molecular weight less than 200.

3. 4', l7fi-dihydroxy [benZo-1',2' 2,3-androstane] 4. 4,17fi bis(Bcyclohexylpropionoxy) [benzo 1', 2 2',3-androstane] 5. 4,l7fi dihydroxy17a methyl[benzo 1',2:2,3 androstane].

6. 43175 dihydroxy 17a methyl[benzo 1',2':2,3 androst-4-ene].

7. 4',17B dihydroxy 17c: methyl[benzo 1',2':2,3 androsta-4,6-diene] 8.4',17fi dihydroxy 17oz ethynyl[benz0 l,2:2,3 androst-4-ene] 9. 4,17a,21trihydrox} 11,20 dioxo[benzo l,2:2, 3-pregn-4-ene] 1 1.4'-hydroXy-20-0xo [benzo- 1 ,2 2,3-pregn-4-ene].

12. A 3',5 dicarbo lower alkoxy 4' hydroxy [benzo-1',2:2,3-steroid], thesteroid moiety having from seventeen to about twenty-three carbon atomsexclusive of ester radicals and being selected from the group consistingof members of the estrane, 18-norestrane, androstane, etiochloane,pregnane and allopregnane series.

13. A 3',5 dicarboxy 4' hydroxy[benzo 1',2':2, 3-steroid], the steroidmoiety having from seventeen to about twenty-three carbon atomsexclusive of ester radicals and being selected from the group consistingof members of the estrane, 18-norestrane, androstane, etiocholane,pregnane and allopregnane series.

14. A compound selected from the group consisting of (A) compoundshaving the formula wherein R is a member of the group consisting ofhydrogen, lower-alkyl, lower-alkenyl, lower-alkynyl, acetyl,hydroxyacetyl, l,2-dihydroxyethyl and l-hydroxyethyl; R is lower-alkyl;X is a member of the group consisting of H (H) (OH) and O; Y and Y aremembers of the group consisting of hydrogen and methyl; and Z is amember of the group consisting of hydrogen and hydroxy, Z beingrestricted to hydro'xy when R is a member of the group consisting ofhydrogen, lower-alkyl, loweralkenyl and loWer-alkynyl; (B) compounds ofthe above formula having a double bond in the 4,5-posit'ion; and (C)compounds of the above formula having two double bonds, one in the4,5-position and the other in the 6,7- position.

15. A compound selected from the group consisting of (A) compoundshaving the formula HO'OC V coon I wherein R is a member of the groupconsisting of hydrogen, lower-alkyl, lower-alkenyl, lower-alkynyl,acetyl, hydroxyacetyl, 1,2-dihy'droxyethyl and l-hydroxyethyl; X is amember of the group consisting of H (H)(OH) and O; Y and Y are membersof the group consisting of hydrogen and methyl; and Z is a member of thegroup consisting of hydrogen and hydroxy, Z being restricted to hydroxywhen R is a member of the group consisting of hydrogen, l'ower-alkyl,lower-alkenyl and lower-alkynyl; (B) compounds of the above formulahaving a double bond in the 4,5-position; and (C) compounds of the aboveformula having two double bonds, one in the 4,5-position and the otherin the 6,7-position.

.16. 3,5' dicarbomethoxy 4',17;8 dihydroxy [benzo 1',2' 2,3-androstane].

17. 3,5 dicarboxy 43175 dihydroxy[benzo 1, 2': 2,3-androstane].

v18. 3',5 dicarboxy 4',l7,8 dihydr'oxy 17cc methyl [benzo-l ',2' 2,S-androstane] 19. 3',5 dicarbomethoxy 4',17/3 dihyd-roXy 17cc methyl[benzo-l ',2. 2,3-androst-4-ene] 20. 3,5 dicarboxy 41176 dihydroxy amethyl [benzo-l ,2' 2,3-androst-4-ene].

21. 3,5' dicarboxy 4,l7fl dihydr'oxy 170a methyl [benzo-l ,2'2,3-androsta-4,6-diene] 22. 3,5' dicarboxy 4',l7/3 dihydroxy 17a ethynyl[benzo-l ,2 2,3-androst-4-ene] 23. A compound having the formula whereinR is lower-a1kyl.

24. 170: methyl 17,8 hydroxy 4 oxo l,4',5',6' tetrahydro [benzo-1',2 2,3-androstane].

25. A process for preparing a 4-hydroxy[benzo-1, 2':2,3-steroid] whichcomprises condensing a 2-hydroxymethylene-3-oxo-steroid with adi-lower-alkyl acetonedicarboxylate in the presence of a strong base,hydrolyzing the resulting 3,5'-dicarbo-lower-alkoxy-4'-hydroxybenzo-l,2:2,3-steroid], and decarboxylating the 3,5- dicarboxy 4hydroxy[benzo 1',2':2,3 steroid] thus formed by heating it with a base,the steroid moiety having from seventeen to about twenty-three carbonatoms exclusive of ester radicals and being selected from the groupconsisting of members of the estrane, 18-norestrane, androstane,etiocholane, pregnane and allopregnane series.

26. A process for preparing a 3',5-dicarbo-loweralkoxy-4'-hydroxy[benzo-12 2,3-steroid] which comprises condensing a2-hydroxymethylene-3-oxo-steroid with a di-lower-alkylacetonedicarboxylate in the presence of a strong base, the steroidmoiety having from seventeen to about twenty-three carbon atomsexclusive of ester radicals and being selected from the group consistingof members of the estrane, 18-norestrane, androstane, etiocholane,pregnane and allopregnane series.

27. A process for preparing a 3,5'-dicarbox-y-4-hydroxy[benzo-1,2':2,3-steroid] which comprises hydrolyzing a 3,5 dicarbo loweralkoxy 4 hydroxy[benzo- 1,2':2,3-steroid], the steroid moiety havingfrom seventeen to about twenty-three carbon atoms exclusive of esterradicals and being selected from the group consisting of members of theestrane, l8-norestrane, androstane, etiocholane, pregnane andallopregnane series.

28. A process for preparing a 4'-hydroxy[benzo-l', 2':2,3-steroid] whichcomprises decarboxylating a 35'-dic-arboxy-4-hydroxy[benzo-1,22,3-steroid] the steroid moiety having from seventeen to abouttwenty-three carbon atoms exclusive of ester radicals and being selectedfrom the group consisting of members of the estrane, 18- norestrane,androstane, etiocholane, pregnane and appopregnane series.

29. A process for preparing a compound selected from the groupconsisting of (A) compounds having the formula ll HO- (B) compounds ofthe immediately above formula having a double bond in the 4,5-position;and (C) compounds of the immediately above formula having two doublebonds, one in the 4,5-position and the other in the 6,7-position,

wherein R is a member of the group consisting of hydrogen, lower-alkyl,loWer-alkenyl, lower-alkynyl, acetyl, hydroxyacetyl, 1,2-dihydroxyethyland l-hydroxyethyl; R is lower-alkyl; X is a member of the groupconsisting of H (H)(OH) and O; Y and Y are members of the groupconsisting of hydrogen and methyl; and Z is a member of the groupconsisting of hydrogen and hydroxy, Z being restricted to hydroxy when Ris a member of the group consisting of hydrogen, lower-alkyl,loWer-alkenyl and loweralkynyl.

30. A process for preparing a compound selected from the groupconsisting of (A) compounds having the formula (3) compounds of theabove formula having a double bond in the 4,5-positiorr; and (C)compounds of the above formula having two double bonds, one in the4,5-position and the other in the 6,7-position, which compriseshydrolyzing a compound selected from the group consisting of (A)compounds having the formula COOR (B) compounds of the immediately aboveformula hav-' ing a double bond in the 4,5-position; and (C) compoundsof the immediately above formula having two double bonds, one in the4,5-position and the other in the 6,7-position, wherein R is a member ofthe group consisting of hydrogen, lower-alkyl, lower-alkenyl,loweralkynyl, acetyl, hydroxyacetyl, 1,2-dihydroxyethyl and 1-hydroxyethyl; R is lower-alkyl; X is a member of the.

group consisting of H (H) (OH) and O; Y and Y are members of the groupconsisting of hydrogen and methyl; and Z is a member of the groupconsisting of hydrogen and hydroxy, Z being restricted to hydroxy when Ris a member of the group consisting of hydrogen, lower-alkyl,loWer-alkenyl and lower-alkynyl.

31. A process for preparing a compound selected from the groupconsisting of (A) compounds having the formula prises decarboxylating acompound selected from the group consisting of (A) compounds having theformula (3) compounds of the immediately above formula having a doublebond in the 4,5-position; and (C) compounds of the immediately aboveformula having two double bonds, one in the 4,5-position and the otherin the 6,7-position, wherein R is a member of the group consisting ofhydrogen, lower-alkyl, loWer-alkenyl, loweraikynyl, acetyl,hydroxyacetyl, 1,2-dihydroxyethyl and 1- nydroxyethyl; X is a member ofthe group consisting of H (H) (OH) and O; Y and Y are members of thegroup consisting of hydrogen and methyl; and Z is a member of the groupconsisting of hydrogen and hydrc-xy, Z being restricted to hydroxy whenR is a member of the group consisting of hydrogen, loWer-alkyl,loweralkenyl and loWer-alkynyl.

32. A process according to claim 31 wherein the decarboxylation iscarried out by heating in quinoline.

33. A process for preparing a compound having the formula HOOO COOH

which comprises treating with methyl vinyl ketone a compound having theformula CH3 I UNITED STATES PATENTS Atwater June 7, 1960 Kincl Feb. 12,1963 OTHER REFERENCES Cooley et al.: J.C.S. (London), September 1960,pages 3676-3 673.

UNITED STATES PATENT OFFICE CERTIFICATE QF CURECTIGN Patent No 3 122,572February 25 1964 Raymond 0 Clinton It is hereby certified that errorappears in the above numbered patent requiring correction and that thesaid Letters Patent should read as corrected below.

Column l line 68, for "C read C column 3 lines 45 to 54 formula VIshould appear as shown below instead of as in the patent:

column l0 line 57 after 1 2 22,3-" insert we androst-5-ene] E bycondensing 2--hydroxymethylene -4, 4 column 17 line 2 for ""l ,3 2 readme -l" .2 2 line 49 for "2" fj read 2 3- column l8 line 54, for ""3 5read me 3 5=-= column 19 lines 39 and 40 for "appopregnane" readallopregnane Signed and sealed this 7th day of July 1964,

(SEAL) Attest:

ERNEST W, SWIDER EDWARD J, BRENNER Attesting Officer Commissioner ofPatents

1. A 4''-HYDROXY(BENZO-1'',2'':2,3-STEROID), THE STEROID MOEITY HAVINGFROM SEVENTEEN TO ABOUT TWENTY-THREE CARBON ATOMS EXCLUSIVE OF ESTERRADICALS AND BEING SELECTED FROM THE GROUP CONSISTING OF MEMBERS OF THEESTRANE, 18-NORESTRANE, ANDROSTANE, ETIOCHOLANE, PREGNANE ANDALLOPREGNANE SERIES.
 14. A COMPOUND SELECTED FROM THE GROUP CONSISTINGOF (A) COMPOUNDS HAVING THE FORMULA